Review Metformin: Taking away the candy for cancer? Mathilde Jalving a,b, * , Jourik A. Gietema a , Joop D. Lefrandt b , Steven de Jong a , Anna K.L. Reyners a , Rijk O.B. Gans b , Elisabeth G.E. de Vries a a Department of Medical Oncology, University Medical Centre Groningen, The Netherlands b Department of Internal Medicine, University Medical Centre Groningen, The Netherlands ARTICLE INFO Article history: Received 7 June 2010 Accepted 7 June 2010 Available online 23 July 2010 Keywords: Metformin Cancer Diabetes mellitus Metabolism AMPK ABSTRACT Metformin is widely used in the treatment of diabetes mellitus type 2 where it reduces insulin resistance and diabetes-related morbidity and mortality. Population-based studies show that metformin treatment is associated with a dose-dependent reduction in cancer risk. The metformin treatment also increases complete pathological tumour response rates following neoadjuvant chemotherapy for breast cancer, suggesting a potential role as an anti-cancer drug. Diabetes mellitus type 2 is associated with insulin resistance, elevated insulin levels and an increased risk of cancer and cancer-related mortality. This increased risk may be explained by activation of the insulin- and insulin-like growth factor (IGF) sig- nalling pathways and increased signalling through the oestrogen receptor. Reversal of these processes through reduction of insulin resistance by the oral anti-diabetic drug met- formin is an attractive anti-cancer strategy. Metformin is an activator of AMP-activated protein kinase (AMPK) which inhibits protein synthesis and gluconeogenesis during cellu- lar stress. The main downstream effect of AMPK activation is the inhibition of mammalian target of rapamycin (mTOR), a downstream effector of growth factor signalling. mTOR is frequently activated in malignant cells and is associated with resistance to anticancer drugs. Furthermore, metformin can induce cell cycle arrest and apoptosis and can reduce growth factor signalling. This review discusses the role of diabetes mellitus type 2 and insu- lin resistance in carcinogenesis, the preclinical rationale and potential mechanisms of met- formin’s anti-cancer effect and the current and future clinical developments of metformin as a novel anti-cancer drug. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction In 1924, the Nobel laureate Otto Heinrich Warburg first hypothesised the existence of a connection between cellular metabolism and malignancy. 1 The signalling pathways con- trolling metabolism and cancer and their interactions are now being unravelled and evidence is accumulating that con- ditions associated with metabolic disturbances, such as dia- betes mellitus type 2, increase cancer risk and adversely influence cancer prognosis. AMP-activated protein kinase (AMPK) is a central cellular energy sensor which may be a crucial factor in the interaction between metabolism and cancer. It has also been implicated in the control of pro-aging signalling pathways, which have 0959-8049/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2010.06.012 * Corresponding author at: Department of Medical Oncology, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Tel.: +31 503612821; fax: +31 503614862. E-mail address: m.jalving@int.umcg.nl (M. Jalving). EUROPEAN JOURNAL OF CANCER 46 (2010) 2369 – 2380 available at www.sciencedirect.com journal homepage: www.ejconline.com